The primary goal of this proposed research is targeted towards demonstrating the commercial utilization of human plasma derived inter- alpha inhibitor proteins (IaIp) an effective therapy of sepsis. IaIp are serine protease inhibitors found normally at high levels in human plasma. The fact that no person with complete absence of IaIp has ever been detected suggests an essential physiological role for these proteins. In patients with severe sepsis, the plasma level of IaIp decrease significantly and the decrease correlates with mortality. We propose that administration of IaIp to restore the imbalance between these natural protective inhibitors and destructive proteases will prevent organ injuries and ultimately reduce sepsis related mortality. Our preliminary animal studies in a sepsis rat model of cecal ligation and puncture (CLP) have demonstrated the beneficial effects of IaIp in maintaining hemodynamic stability, preventing organ injury, and improving survival during sepsis. In this study, we propose to optimize a protocol for purification of IaIp from human crude plasma and to evaluate and confirm the beneficial effects of the purified IaIp in the CLP rat model. The ultimate goal of these studies is to develop a novel plasma derived therapeutic that is safe and effective for sepsis. PROPOSED COMMERCIAL APPLICATIONS: There is a serious unmet medical need for more than 1.5 million people worldwide annually who suffer from sepsis. Since there are currently no agents effective for sepsis, treatment is limited to antibiotic and supportive therapy. The magnitude of the need for an effective novel therapeutic agent in reducing sepsis mortality and morbidity is immense and it creates an enormous market potential estimated at $10-25 billion/year in the US alone. Inter-alpha inhibitor proteins appear to be an effective therapeutic agent of sepsis. The proposed study is expected to lead to the development of novel human plasma derived protein that is safe and effective for sepsis.